The present invention is concerned with thiazolyl-benzimidazole derivatives and their pharmaceutically acceptable salts, the manufacture of the aforesaid and their use as therapeutic agents.
PLK1 is a member of the Polo-like kinase family. Polo-like kinases are highly conserved from yeast to humans and play a variety of roles in the G2/M phase transition and in the passage through mitotic phase of the cell cycle. Four Polo-like kinases, PLK1, PLK2 (Snk), PLK3 (Fnk), and PLK4 have been identified in humans. These proteins share extensive homologies across their kinase domains, in C-terminal “Polo” boxes. Using neutralizing antibodies, anti-sense oligos, and dominant-negative protein, PLK1 was shown to be essential for mitosis in vitro cultured cells. Furthermore, down regulation of PLK1 appears to have differential effects in tumor versus “normal” cells in that ablation of PLK1 induced mitotic catastrophe and eventual cell death but G2 arrest in “normal” cells. One plausible explanation is that tumor cells are defective in checkpoint controls and unable to arrest and thus undergo mitotic catastrophe. The roles of PLK2, PLK3, and PLK4 remain elusive.
The expression of PLK1 is restricted to proliferative tissues. Overexpression of PLK1 was detected in solid tumors of various origins (breast, lung, colon, stomach, ovary, smooth muscle, and esophagus) and in non-Hodgkin lymphomas. Furthermore PLK1 has transforming activity; constitutive expression of PLK1 in NIH3T3 cells causes oncogenic focus formation, transformed cells grow in soft agar and form tumors in nude mice.
Therefore, blocking PLK1 kinase activity by a small molecule inhibitor represents a novel approach to target mitosis and may be clearly differentiated from other mitosis-targeting agents on the market such as tubulin binders.
Other therapies which involve the disruption of microtubule formation and degradation through the use of taxanes and vinca alkaloids have become successful ways of treating cancer. Some cancerous cells are able to evade the G2/M cell cycle arrest effect of taxanes and vinca alkaloids. PLK1 inhibition provides a means to target those cells which are able to evade the G2/M cell cycle arresting effect of taxanes and vinca alkaloids.
U.S. Pat. No. 4,818,270 discloses structurally unrelated benzimidazole-thiazole compounds for use as herbicides.
WO200212242 discloses bicyclo-pyrazole compounds that are inhibitors of PLK1. WO200262804 discloses oxazolyl-pyrazole derivatives that are inhibitors of PLK1. WO2003070283 discloses duplex RNAs antisense oligonucleotides that are inhibitors of PLK1. WO2003072062 discloses (E)-2.6-dialkoxystyryl-4-substituted benzylsulfones that are inhibitors of PLK1. WO2003093249 discloses thiazolidinone compounds that are inhibitors of PLK1. WO2004011610 discloses antisense compounds that are inhibitors of PLK1. WO2004014899 discloses thiophene compounds that are inhibitors of PLK1. WO2004043936 discloses pyrimidine compounds that are inhibitors of PLK1. WO2004046317 discloses products and processes for modulating peptide-peptide binding domain interactions including an invention for providing 3-D structures of PLK. WO2004067000 discloses benzothiazole-3-oxides that are inhibitors of PLK1. WO2004074244 discloses pyrimidine compounds that are inhibitors of PLK1. WO2004087652 discloses imidazotriazine compounds that are inhibitors of PLK1. WO2005019193 discloses phenylurea compounds that are inhibitors of PLK1. WO2005042505 discloses thiazolidinones that are inhibitors of PLK1. WO2005042525 discloses pyrimidin-4-yl-3,4-thione compounds that are inhibitors of PLK1. WO2005075470 discloses thiazole compounds that are inhibitors of PLK1.